Scott W. Lowe: Research Overview

Scott W. Lowe: Research Overview

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About the Scott Lowe Lab

Our laboratory studies tumor-suppressor networks controlling apoptosis and senescence and how their disruption influences malignant behavior.

Scott Lowe Lab Plasmid and Animal Requests

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For plasmids not listed on addgene, please contact the lab manager, Anne Trumble-Koncelik, [email protected].

For animal requests, please contact the mouse colony manager, Janelle Simon, [email protected].

Understanding and Exploiting Natural Barriers to Cancer

Cancer arises through an evolutionary process whereby normal cells acquire mutations that erode growth controls. Still, cancer is not an inevitable consequence of mutation, but is kept in check by intrinsic tumor-suppressor programs activated in damaged cells. We study such programs to reveal, and ultimately exploit, the strategies nature uses to combat cancer.

Our early studies focused on cell-intrinsic programs that prevent tumorigenesis (e.g., apoptosis, senescence), and have broadened to cell-extrinsic mechanisms (e.g., immune surveillance). New areas of interest include how tumor-suppressive programs are blunted by environmental factors known to increase cancer incidence (e.g., obesity, aging) and how excessive activation of tumor-suppressive programs (e.g., senescence) can harm function of normal tissue. To gain a mechanistic understanding of these phenomena, we apply mouse models in which cancer arises in an intact tissue ecosystem, which is a long-standing strength of our program. Our affiliation with Memorial Sloan Kettering Cancer Center enables us to probe human systems as well.

Another major goal is to harness our knowledge of tumor suppression therapeutically. We and others have shown that reengaging tumor-suppressive programs in established cancer cells can coordinate tumor regression through both cell-intrinsic and cell-extrinsic components (1-5), so these programs represent attractive strategies for tumor control. With Michel Sadelain, we have also developed a cell therapy approach to remove excessive senescent cells from tissues (6); this therapy may have beneficial effects on cancer and non-cancer pathologies. Advancing these concepts are major goals of our current research.

 

References

1.      Martins CP, Brown-Swigart L, Evan GI. Modeling the therapeutic efficacy of p53 restoration in tumors. Cell. 2006;127(7):1323-34.

2.      Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, Newman J, Reczek EE, Weissleder R, Jacks T. Restoration of p53 function leads to tumour regression in vivo. Nature. 2007;445(7128):661-5.

3.      Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 2007;445(7128):656-60.

4.      Feldser DM, Kostova KK, Winslow MM, Taylor SE, Cashman C, Whittaker CA, Sanchez-Rivera FJ, Resnick R, Bronson R, Hemann MT, Jacks T. Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature. 2010;468(7323):572-5.

5.      Morris JPt, Yashinskie JJ, Koche R, Chandwani R, Tian S, Chen CC, Baslan T, Marinkovic ZS, Sánchez-Rivera FJ, Leach SD, Carmona-Fontaine C, Thompson CB, Finley LWS, Lowe SW. α-Ketoglutarate links p53 to cell fate during tumour suppression. Nature. 2019;573(7775):595-9.

6.      Amor C, Feucht J, Leibold J, Ho YJ, Zhu C, Alonso-Curbelo D, Mansilla-Soto J, Boyer JA, Li X, Giavridis T, Kulick A, Houlihan S, Peerschke E, Friedman SL, Ponomarev V, Piersigilli A, Sadelain M, Lowe SW. Senolytic CAR T cells reverse senescence-associated pathologies. Nature. 2020;583(7814):127-32.