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4. MAD1 upregulation sensitizes to inflammation-mediated tumor formation.

Author

Copeland, Sarah E., Snow, Santina M., Wan, Jun, Matkowskyj, Kristina A., Halberg, Richard B., and Weaver, Beth A.

Subjects
TUMOR suppressor proteins, GENE expression, COLON cancer, SPINDLE apparatus, CHROMOSOME segregation, ADENOMATOUS polyps
Abstract

Mitotic Arrest Deficient 1 (gene name MAD1L1), an essential component of the mitotic spindle assembly checkpoint, is frequently overexpressed in colon cancer, which correlates with poor disease-free survival. MAD1 upregulation induces two phenotypes associated with tumor promotion in tissue culture cells–low rates of chromosomal instability (CIN) and destabilization of the tumor suppressor p53. Using CRISPR/Cas9 gene editing, we generated a novel mouse model by inserting a doxycycline (dox)-inducible promoter and HA tag into the endogenous mouse Mad1l1 gene, enabling inducible expression of HA-MAD1 following exposure to dox in the presence of the reverse tet transactivator (rtTA). A modest 2-fold overexpression of MAD1 in murine colon resulted in decreased p53 expression and increased mitotic defects consistent with CIN. After exposure to the colon-specific inflammatory agent dextran sulfate sodium (DSS), 31% of mice developed colon lesions, including a mucinous adenocarcinoma, while none formed in control animals. Lesion incidence was particularly high in male mice, 57% of which developed at least one hyperplastic polyp, adenoma or adenocarcinoma in the colon. Notably, mice expressing HA-MAD1 also developed lesions in tissues in which DSS is not expected to induce inflammation. These findings demonstrate that MAD1 upregulation is sufficient to promote colon tumorigenesis in the context of inflammation in immune-competent mice. Author summary: Worldwide, colorectal cancer is the third most commonly diagnosed cancer and the second-highest cause of cancer-related deaths. A better understanding of the molecular causes of colorectal cancer could provide novel therapeutic targets for this disease. Mitotic Arrest Deficient-1 (MAD1) is commonly overexpressed in colorectal cancers, and elevated expression of MAD1 is associated with worse prognosis. Here we generated a new mutant mouse with inducible, modest overexpression of MAD1. First identified for its role in mitosis, MAD1 is required to ensure proper chromosome segregation. Elevated expression of MAD1 causes chromosome mis-segregation in the colons of these mice. During interphase, overexpressed MAD1 destabilizes the well-known tumor suppressor protein, p53. Consistent with this, mouse colons modestly overexpressing MAD1 show decreased expression of p53. Since inflammation is a risk factor for colorectal cancer, we induced inflammation in the colon using dextran sulfate sodium (DSS) and found that MAD1 overexpression significantly increased the incidence of colon tumors. Like inflammation-mediated colon tumors in humans, in the mice these tumors were more common in males than females. This work shows that MAD1 overexpression can promote colon cancer and suggests that MAD1 may be a novel drug target for this disease. [ABSTRACT FROM AUTHOR]

Published
2024
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14. Data from Colon Tumors with the Simultaneous Induction of Driver Mutations in APC, KRAS, and PIK3CA Still Progress through the Adenoma-to-carcinoma Sequence

Author

Hadac, Jamie N., primary, Leystra, Alyssa A., primary, Paul Olson, Terrah J., primary, Maher, Molly E., primary, Payne, Susan N., primary, Yueh, Alexander E., primary, Schwartz, Alexander R., primary, Albrecht, Dawn M., primary, Clipson, Linda, primary, Pasch, Cheri A., primary, Matkowskyj, Kristina A., primary, Halberg, Richard B., primary, and Deming, Dustin A., primary

Published
2023
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15. Supplementary Figure Legends from Colon Tumors with the Simultaneous Induction of Driver Mutations in APC, KRAS, and PIK3CA Still Progress through the Adenoma-to-carcinoma Sequence

Author

Hadac, Jamie N., primary, Leystra, Alyssa A., primary, Paul Olson, Terrah J., primary, Maher, Molly E., primary, Payne, Susan N., primary, Yueh, Alexander E., primary, Schwartz, Alexander R., primary, Albrecht, Dawn M., primary, Clipson, Linda, primary, Pasch, Cheri A., primary, Matkowskyj, Kristina A., primary, Halberg, Richard B., primary, and Deming, Dustin A., primary

Published
2023
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16. Supplementary Figure S2 from Colon Tumors with the Simultaneous Induction of Driver Mutations in APC, KRAS, and PIK3CA Still Progress through the Adenoma-to-carcinoma Sequence

Author

Hadac, Jamie N., primary, Leystra, Alyssa A., primary, Paul Olson, Terrah J., primary, Maher, Molly E., primary, Payne, Susan N., primary, Yueh, Alexander E., primary, Schwartz, Alexander R., primary, Albrecht, Dawn M., primary, Clipson, Linda, primary, Pasch, Cheri A., primary, Matkowskyj, Kristina A., primary, Halberg, Richard B., primary, and Deming, Dustin A., primary

Published
2023
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17. Supplementary Table 3 from Dynamic Tumor Growth Patterns in a Novel Murine Model of Colorectal Cancer

Author

Paul Olson, Terrah J., primary, Hadac, Jamie N., primary, Sievers, Chelsie K., primary, Leystra, Alyssa A., primary, Deming, Dustin A., primary, Zahm, Christopher D., primary, Albrecht, Dawn M., primary, Nomura, Alice, primary, Nettekoven, Laura A., primary, Plesh, Lauren K., primary, Clipson, Linda, primary, Sullivan, Ruth, primary, Newton, Michael A., primary, Schelman, William R., primary, and Halberg, Richard B., primary

Published
2023
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18. Supplementary Table 2 from Dynamic Tumor Growth Patterns in a Novel Murine Model of Colorectal Cancer

Author

Paul Olson, Terrah J., primary, Hadac, Jamie N., primary, Sievers, Chelsie K., primary, Leystra, Alyssa A., primary, Deming, Dustin A., primary, Zahm, Christopher D., primary, Albrecht, Dawn M., primary, Nomura, Alice, primary, Nettekoven, Laura A., primary, Plesh, Lauren K., primary, Clipson, Linda, primary, Sullivan, Ruth, primary, Newton, Michael A., primary, Schelman, William R., primary, and Halberg, Richard B., primary

Published
2023
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19. Supplementary Figure 1 from Dynamic Tumor Growth Patterns in a Novel Murine Model of Colorectal Cancer

Author

Paul Olson, Terrah J., primary, Hadac, Jamie N., primary, Sievers, Chelsie K., primary, Leystra, Alyssa A., primary, Deming, Dustin A., primary, Zahm, Christopher D., primary, Albrecht, Dawn M., primary, Nomura, Alice, primary, Nettekoven, Laura A., primary, Plesh, Lauren K., primary, Clipson, Linda, primary, Sullivan, Ruth, primary, Newton, Michael A., primary, Schelman, William R., primary, and Halberg, Richard B., primary

Published
2023
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20. Data from Dynamic Tumor Growth Patterns in a Novel Murine Model of Colorectal Cancer

Author

Paul Olson, Terrah J., primary, Hadac, Jamie N., primary, Sievers, Chelsie K., primary, Leystra, Alyssa A., primary, Deming, Dustin A., primary, Zahm, Christopher D., primary, Albrecht, Dawn M., primary, Nomura, Alice, primary, Nettekoven, Laura A., primary, Plesh, Lauren K., primary, Clipson, Linda, primary, Sullivan, Ruth, primary, Newton, Michael A., primary, Schelman, William R., primary, and Halberg, Richard B., primary

Published
2023
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21. Supplementary Table 1 from Dynamic Tumor Growth Patterns in a Novel Murine Model of Colorectal Cancer

Author

Paul Olson, Terrah J., primary, Hadac, Jamie N., primary, Sievers, Chelsie K., primary, Leystra, Alyssa A., primary, Deming, Dustin A., primary, Zahm, Christopher D., primary, Albrecht, Dawn M., primary, Nomura, Alice, primary, Nettekoven, Laura A., primary, Plesh, Lauren K., primary, Clipson, Linda, primary, Sullivan, Ruth, primary, Newton, Michael A., primary, Schelman, William R., primary, and Halberg, Richard B., primary

Published
2023
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22. Supplementary Figure 2 from Dynamic Tumor Growth Patterns in a Novel Murine Model of Colorectal Cancer

Author

Paul Olson, Terrah J., primary, Hadac, Jamie N., primary, Sievers, Chelsie K., primary, Leystra, Alyssa A., primary, Deming, Dustin A., primary, Zahm, Christopher D., primary, Albrecht, Dawn M., primary, Nomura, Alice, primary, Nettekoven, Laura A., primary, Plesh, Lauren K., primary, Clipson, Linda, primary, Sullivan, Ruth, primary, Newton, Michael A., primary, Schelman, William R., primary, and Halberg, Richard B., primary

Published
2023
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23. Supplementary Table 1 from Colon Tumors with the Simultaneous Induction of Driver Mutations in APC, KRAS, and PIK3CA Still Progress through the Adenoma-to-carcinoma Sequence

Author

Hadac, Jamie N., primary, Leystra, Alyssa A., primary, Paul Olson, Terrah J., primary, Maher, Molly E., primary, Payne, Susan N., primary, Yueh, Alexander E., primary, Schwartz, Alexander R., primary, Albrecht, Dawn M., primary, Clipson, Linda, primary, Pasch, Cheri A., primary, Matkowskyj, Kristina A., primary, Halberg, Richard B., primary, and Deming, Dustin A., primary

Published
2023
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24. Data from Mice Expressing Activated PI3K Rapidly Develop Advanced Colon Cancer

Author

Leystra, Alyssa A., primary, Deming, Dustin A., primary, Zahm, Christopher D., primary, Farhoud, Mohammed, primary, Olson, Terrah J. Paul, primary, Hadac, Jamie N., primary, Nettekoven, Laura A., primary, Albrecht, Dawn M., primary, Clipson, Linda, primary, Sullivan, Ruth, primary, Washington, Mary Kay, primary, Torrealba, Jose R., primary, Weichert, Jamey P., primary, and Halberg, Richard B., primary

Published
2023
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25. Supplementary Movie from Mice Expressing Activated PI3K Rapidly Develop Advanced Colon Cancer

Author

Leystra, Alyssa A., primary, Deming, Dustin A., primary, Zahm, Christopher D., primary, Farhoud, Mohammed, primary, Olson, Terrah J. Paul, primary, Hadac, Jamie N., primary, Nettekoven, Laura A., primary, Albrecht, Dawn M., primary, Clipson, Linda, primary, Sullivan, Ruth, primary, Washington, Mary Kay, primary, Torrealba, Jose R., primary, Weichert, Jamey P., primary, and Halberg, Richard B., primary

Published
2023
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26. Supplementary Figures 1-7 from Mice Expressing Activated PI3K Rapidly Develop Advanced Colon Cancer

Author

Leystra, Alyssa A., primary, Deming, Dustin A., primary, Zahm, Christopher D., primary, Farhoud, Mohammed, primary, Olson, Terrah J. Paul, primary, Hadac, Jamie N., primary, Nettekoven, Laura A., primary, Albrecht, Dawn M., primary, Clipson, Linda, primary, Sullivan, Ruth, primary, Washington, Mary Kay, primary, Torrealba, Jose R., primary, Weichert, Jamey P., primary, and Halberg, Richard B., primary

Published
2023
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29. Identifying Carriers of a Genetic Modifier Using Nonparametric Bayesian Methods

Author

Hoff, Peter D., Halberg, Richard B., Shedlovsky, Alexandra, Dove, William F., Newton, Michael A., Bickel, P., editor, Diggle, P., editor, Fienberg, S., editor, Krickeberg, K., editor, Olkin, I., editor, Wermuth, N., editor, Zeger, S., editor, Gatsonis, Constantine, editor, Kass, Robert E., editor, Carlin, Bradley, editor, Carriquiry, Alicia, editor, Gelman, Andrew, editor, Verdinelli, Isabella, editor, and West, Mike, editor

Published
2002
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34. Validation of genetic classifiers derived from mouse and human tumors to identify molecular subtypes of colorectal cancer

Author

Snow, Santina M., primary, Matkowskyj, Kristina A., additional, Maresh, Morgan, additional, Clipson, Linda, additional, Vo, Tien N., additional, Johnson, Katherine A., additional, Deming, Dustin A., additional, Newton, Michael A., additional, Grady, William M., additional, Pickhardt, Perry J., additional, and Halberg, Richard B., additional

Published
2022
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36. Multi‐ancestral origin of intestinal tumors: Impact on growth, progression, and drug efficacy

Author

Leystra, Alyssa A., primary, Gilsdorf, Brock J., additional, Wisinger, Amanda M., additional, Warda, Elise R., additional, Wiegand, Shanna, additional, Zahm, Christopher D., additional, Matkowskyj, Kristina A., additional, Deming, Dustin A., additional, Khan, Naghma, additional, Rosemarie, Quincy, additional, Sievers, Chelsie K., additional, Schwartz, Alexander R., additional, Albrecht, Dawn M., additional, Clipson, Linda, additional, Mukhtar, Hasan, additional, Newton, Michael A., additional, and Halberg, Richard B., additional

Published
2021
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41. Tumor aggressiveness is independent of radiation quality in murine hepatocellular carcinoma and mammary tumor models

Author

Udho, Eshwar B., primary, Huebner, Shane M., additional, Albrecht, Dawn M., additional, Matkowskyj, Kristina A., additional, Clipson, Linda, additional, Hedican, Catigan A., additional, Koth, Rachel, additional, Snow, Santina M., additional, Eberhardt, Emily L., additional, Miller, Devon, additional, Van Doorn, Rachel, additional, Gjyzeli, Genti, additional, Spengler, Erin K., additional, Storts, Douglas R., additional, Thamm, Douglas H., additional, Edmondson, Elijah F., additional, Weil, Michael M., additional, Halberg, Richard B., additional, and Bacher, Jeffery W., additional

Published
2021
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42. The pleiotropic phenotype of Apc mutations in the mouse: allele specificity and effects of the genetic background

Author

Halberg, Richard B., Chen, Xiaodi, Amos-Landgraf, James M., White, Alanna, Rasmussen, Kristin, Clipson, Linda, Pasch, Cheri, Sullivan, Ruth, Pitot, Henry C., and Dove, William F.

Subjects
Pleiotropy -- Evaluation, Phenotype -- Identification and classification, Gene mutations -- Identification and classification, Allelomorphism -- Identification and classification, Biological sciences
Abstract

Familial adenomatous polyposis (FAP) is a human cancer syndrome characterized by the development of hundreds to thousands of colonic polyps and extracolonic lesions including desmoid fibromas, osteomas, epidermoid cysts, and congenital hypertrophy of the pigmented retinal epithelium. Afflicted individuals are heterozygous for mutations in the APC gene. Detailed investigations of mice heterozygous for mutations in the ortholog Apc have shown that other genetic factors strongly influence the phenotype. Here we report qualitative and quantitative modifications of the phenotype of Ape mutants as a function of three genetic variables: Apc allele, p53 allele, and genetic background. We have found major differences between the Ape alleles Min and 1638N in multiplicity and regionality of intestinal tumors, as well as in incidence of extracolonic lesions. By contrast, Min mice homozygous for either of two different knockout alleles of p53 show similar phenotypic effects. These studies illustrate the classic principle that functional genetics is enriched by assessing penetrance and expressivity with allelic series. The mouse permits study of an allelic gene series on multiple genetic backgrounds, thereby leading to a better understanding of gene action in a range of biological processes.

Published
2008

50. Prostate epithelial‐specific expression of activated PI3K drives stromal collagen production and accumulation

Author

Wegner, Kyle A, primary, Mueller, Brett R, additional, Unterberger, Christopher J, additional, Avila, Enrique J, additional, Ruetten, Hannah, additional, Turco, Anne E, additional, Oakes, Steven R, additional, Girardi, Nicholas M, additional, Halberg, Richard B, additional, Swanson, Steven M, additional, Marker, Paul C, additional, and Vezina, Chad M, additional

Published
2019
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