Lisa Maria Mustachio

• Doctor of Philosophy
• Institute Research Investigator at University of Texas MD Anderson Cancer Center

Cancer metastasis is a major cause of cancer-related mortality. Strategies to reduce metastases are needed especially in lung cancer, the most common cause of cancer mortality. We previously reported increased ubiquitin-specific peptidase 18 (USP18) expression in lung and other cancers. Engineered reduction of USP18 expression repressed lung cancer...

Single-cell sequencing encompasses a variety of technologies that evaluate cells at the genomic, transcriptomic, epigenomic, and proteomic levels. Each of these levels can be split into additional techniques that enable specific and optimized sequencing for a specialized purpose. At the transcriptomic level, single-cell sequencing has been used to...

Soft tissue sarcomas, depending on the subtype and grade, frequently recur and become metastatic after localized treatment. There is now great interest in applying immunotherapy to sarcomas to immuno-profile the different subtypes and immune monitor for prognosis. Our group previously showed that key immunotherapy target genes are present in sarcom...

Usp22 overexpression is observed in several human cancers and is correlated with poor patient outcomes. The molecular basis underlying this correlation is not clear. Usp22 is the catalytic subunit of the deubiquitylation module in the SAGA histone-modifying complex, which regulates gene transcription. Our previous work demonstrated that the loss of...

Simple Summary Since the Kirsten rat sarcoma viral oncogene homolog (KRAS) is mutated in about 25% of all human cancers and is at the center of pathways involved in tumorigenesis, it is necessary to compile and highlight the novel therapeutic strategies behind targeting this oncoprotein in cancer. Over the years, many have studied various methods t...

h3> Ubiquitin specific peptidase 18 (USP18), previously known as UBP43, is the IFN-stimulated gene 15 (ISG15) deconjugase. USP18 removes ISG15 from substrate proteins. This study reports that USP18-null mice (vs. wild-type mice) exhibited lower lipolysis rates, altered fat to body weight ratios, and cold sensitivity. USP18 is a regulator of lipid...

Cyclin dependent kinase 2 (CDK2) antagonism inhibits clustering of excessive centrosomes at mitosis, causing multipolar cell division and apoptotic death. This is called anaphase catastrophe. To establish induced anaphase catastrophe as a clinically-tractable anti-neoplastic mechanism, induced anaphase catastrophe was explored in different aneuploi...

This Special Issue on “Single-cell Data Science” aims to highlight recent advances in the area of single-cell sequencing technologies and data analytics [...]

Lung cancers contribute to the greatest number of cancer-related deaths worldwide and still pose challenges in response to current treatment strategies. Non-small cell lung cancer (NSCLC) accounts for over 85% of lung cancers diagnosed in the United States and novel therapeutics are needed for the treatment of this disease. First and second generat...

Ubiquitin specific peptidase 18 (USP18) is the Interferon-Stimulated Gene 15 (ISG15) deconjugase that stabilizes target proteins by removing ISG15 from substrate proteins. We found that USP18 null mice have lower lipolysis rates, altered fat to body weight ratios and marked cold sensitivity. These findings implicated USP18 as a regulator of lipid a...

Targeting epigenetic regulators such as histone modifying enzymes provides novel strategies for cancer therapy. The GCN5 lysine acetyltransferase (KAT) functions together with MYC both during normal development and in oncogenesis. As transcription factors, MYC family members are difficult to target with small molecule inhibitors, but the acetyltran...

GCN5, the catalytic subunit in the acetyltransferase modules of SAGA and ATAC, functions as a coactivator of gene transcription. The SAGA complex is recruited to chromatin by transcription factors such as MYC and E2F1 to facilitate acetylation of histones, especially H3 at lysine 9 (H3K9). Burkitt lymphoma is an aggressive subtype of Non-Hodgkin ly...

Lung cancer causes the highest mortality in cancer-related deaths. As these cancers often become resistant to existing therapies, definition of novel molecular targets is needed. Epigenetic modifiers may provide such targets. Recent reports suggest that the histone acetyltransferase (HAT) module within the transcriptional coactivator SAGA complex p...

The spindle assembly checkpoint (SAC) maintains genomic integrity. A key component is threonine tyrosine kinase (TTK, also known as Mps1). TTK antagonism is hypothesized to cause genomic instability and cell death. Interrogating The Cancer Genome Atlas (TCGA) revealed high TTK expression in lung adenocarcinomas and squamous cell cancers versus the...

Metastasis is a major cause of cancer-related mortality. Yet, current antineoplastic strategies do not effectively repress metastasis. Thus, there is a pressing need to explore targets that can reduce metastasis, especially in lung cancer that is the most common cause of cancer mortality. Our prior work reported that expression of the ubiquitin-spe...

Genetically-unstable cancer cells have supernumerary centrosomes and aneuploidy (a hallmark of cancer). CDK2 antagonism inhibits clustering of excessive centrosomes at mitosis leading to multipolar cell division and apoptotic death. This process is called anaphase catastrophe. Anaphase catastrophe affects preferentially aneuploid cancer cells while...

Lung cancer causes the highest mortality in cancer-related deaths. Definition of novel molecular targets is needed since these cancers often become resistant to existing therapies. Epigenetic modifications may provide such targets. Recent reports suggest that the histone acetyltransferase (HAT) module within the transcriptional coactivator SAGA com...

Metastasis is a major cause of cancer-related mortality. Yet, current antineoplastic strategies do not effectively repress metastasis. Thus, there is a pressing need to explore targets that can reduce metastasis, especially in lung cancer that is the most common cause of cancer mortality. Our prior work reported that expression of the ubiquitin-spe...

Lung cancer causes the highest mortality in cancer-related deaths. Definition of novel molecular targets is needed since these cancers often become resistant to existing therapies. Epigenetic modifications may provide such targets. Recent reports suggest that the histone acetyltransferase (HAT) module within the transcriptional coactivator SAGA com...

Genetically-unstable cancer cells have supernumerary centrosomes and aneuploidy (a hallmark of cancer). CDK2 antagonism inhibits clustering of excessive centrosomes at mitosis leading to multipolar cell division and apoptotic death. This process is called anaphase catastrophe. Anaphase catastrophe affects preferentially aneuploid cancer cells while...

Lung cancer causes the highest mortality in cancer-related deaths. Definition of novel molecular targets is needed since these cancers often become resistant to existing therapies. Epigenetic modifications may provide such targets. Recent reports suggest that the histone acetyltransferase (HAT) module within the transcriptional coactivator SAGA com...

USP18 is the ISG15 (Interferon-Stimulated Gene 15) deconjugase that removes ISG15 from substrate proteins. We found USP18 null mice are markedly cold sensitive versus their wild-type littermates. USP18 null mice had significantly (P < 0.05) greater temperature declines than wild-type mice. These mice also had lower lipolysis rates and altered fat t...

Despite current treatments, lung cancers remain a major public health problem. Innovative ways are needed to treat or prevent these cancers. Centrosomes are critical for fidelity of mitosis. Abnormal centrosome numbers can cause aberrant mitosis and cell death. Polo-like kinase 4 (PLK4) is a serine/threonine kinase regulating centriole duplication...

Cancer cells often have supernumerary centrosomes that promote genomic instability, a pathognomonic feature of cancer. During mitosis, cancer cells with supernumerary centrosomes undergo bipolar cell division by clustering centrosomes into two poles. When supernumerary centrosome clustering is antagonized, cancer cells are forced to undergo multipo...

Significance Despite current treatments, lung cancers remain a major public health problem. Innovative ways are needed to treat or prevent these cancers. Centrosomes are critical for fidelity of mitosis. Abnormal centrosome numbers can cause aberrant mitosis and cell death. Polo-like kinase 4 (PLK4) regulates centriole duplication, and its deregula...

Ubiquitination and ubiquitin-like posttranslational modifications (PTM) regulate activity and stability of oncoproteins and tumor suppressors. This implicates PTMs as antineoplastic targets. One way to alter PTMs is to inhibit activity of deubiquitinases (DUB) that remove ubiquitin or ubiquitin-like proteins from substrate proteins. Roles of DUBs i...

We previously reported CDK2 antagonism with the first generation CDK2/9/7 inhibitor seliciclib (CYC202; Cyclacel) triggered anaphase catastrophe. This occurred when genomically unstable cancer cells with supernumerary centrosomes (a hallmark of cancer) fail to cluster excessive centrosomes at mitosis. This causes multipolar cell division and apopto...

Metastasis is a major cause of human lung cancer mortality. Uncovering novel targets and mechanisms involved in regulating metastasis is critical for developing effective ways to improve lung cancer survival. It is reported that ubiquitin and ubiquitin-like pathways can regulate invasion and metastasis. We previously found that USP18 (Ubiquitin Spe...

Background: The first generation CDK2/7/9 inhibitor seliciclib (CYC202) causes multipolar anaphase and apoptosis in lung cancer cells with supernumerary centrosomes (known as anaphase catastrophe). We investigated a new and potent CDK2/9 inhibitor, CCT68127 (Cyclacel). Methods: CCT68127 was studied in lung cancer cells (three murine and five human)...

KRAS is frequently mutated in lung cancers and is associated with aggressive biology and chemotherapy resistance. Therefore, innovative approaches are needed to treat these lung cancers. Prior work implicated the IFN-stimulated gene 15 (ISG15) deubiquitinase (DUB) USP18 as having antineoplastic activity by regulating lung cancer growth and oncoprot...

The ubiquitin-like modifier interferon-stimulated gene 15 (ISG15) is implicated in both oncogenic and tumor suppressive programs. Yet, few ISGylation substrates are known and functionally validated in cancer biology. We previously found specific oncoproteins were substrates of ISGylation and were stabilized by the ISG15-specific deubiquitinase (DUB...

Despite advances in targeted therapy, lung cancer remains the most common cause of cancer-related mortality in the United States. Chromosomal instability is a prominent feature in lung cancer and because it rarely occurs in normal cells, it represents a potential therapeutic target. Our prior work discovered that lung cancer cells undergo anaphase...

KRAS is frequently mutated in lung cancers. Innovative strategies are needed to combat KRAS mutant lung cancers because these tumors are often resistant to therapy. This study reports that loss of the deubiquitinase USP18 leads to destabilization of the KRAS oncogenic protein in panels of murine and human lung cancer cells. In marked contrast, engi...

We reported the first generation CDK2/9/7 inhibitor seliciclib (R-roscovitine, CYC202) exerts antineoplastic effects against lung cancer by inducing anaphase catastrophe. In anaphase catastrophe, cells with aneuploidy (a hallmark of cancer) cannot cluster supernumerary centrosomes, triggering abnormal anaphase and apoptosis. This study now finds th...

Chromosomal instability (CIN) is a hallmark of solid tumor biology and is implicated in carcinogenesis. Preferentially eliminating malignant cells by targeting CIN and aneuploidy is an attractive anti-neoplastic strategy. We previously reported that CDK2 antagonism causes lung cancer cells to undergo anaphase catastrophe and apoptosis through inhib...

Our prior work revealed the first generation CDK2/9/7 inhibitor seliciclib (R-roscovitine, CYC202) significantly inhibited lung cancer growth and tumorigenicity by increasing apoptosis via induced anaphase catastrophe. In anaphase catastrophe, cells with aneuploidy (a hallmark of cancer), cannot cluster supernumerary centrosomes. This triggers abno...

Aneuploidy is frequently detected in human cancers and is implicated in carcinogenesis. Pharmacological targeting of aneuploidy is an attractive therapeutic strategy as this would preferentially eliminate malignant over normal cells. We previously discovered that CDK2 inhibition causes lung cancer cells with more than two centrosomes to undergo mul...

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA KRAS is frequently mutated in human lung cancers. Lung cancers with mutant KRAS are often resistant to current therapies. There is therefore a need to develop new ways to target these tumors with KRAS mutations. We previously found that the protein modification pathway containin...

Aneuploidy is frequently detected in human cancers and is implicated in carcinogenesis. Whether aneuploidy is an anti-neoplastic target remains to be learnt. We previously uncovered an unrecognized consequence of Cdk2 inhibition that causes lung cancer cells to undergo anaphase catastrophe, growth inhibition and apoptosis. Cells with activating KRA...

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC The interferon stimulated protein ISG15 was one of the first ubiquitin-like modifiers discovered. Similar to ubiquitin, ISG15 is conjugated to cellular proteins through a three-step enzymatic cascade involving an activating enzyme E1 (UBE1L), a conjugating enzyme E2 and a...

Age-related thymic involution is characterized by a progressive regression in thymus size and a diminishment of thymic structure. A decrease in thymic compartments leads to the reduction of thymopoiesis. Thymic involution is closely associated with immunosenescence, a degeneration of the immune system primarily due to the alterations in T-cell comp...

Vibrio cholerae continues to pose a health threat in many developing nations and regions of the world struck by natural disasters. It is a pathogen that rapidly adapts to aquatic environments and the human small intestine. Small regulatory RNAs (sRNAs) may contribute to this adaptability. Specifically, the mannitol operon sRNA (MtlS sRNA; previousl...