Cancer in the neighborhood
Cancer cells hijack their environment to promote their initiation, growth and spread.
Fundamental changes in our cells and tissues occur with age—and age is a well-recognized risk factor for most adult cancers. These changes to both emergent cancer cells and their neighboring tissues promote cancers in the elderly. Once tumors form, they can manipulate their tissue environment and fool the immune system to escape detection and can even mobilize immune cells to promote their growth. Over time, tumors that do respond to treatment can adapt and become resistant to a therapy that once worked.
We are defining the changes in cells and their environment that predispose them to cancer and how these changes are affected in aged tissues by studying the cross-talk between cancer cells, immune cells and stromal components that regulate the growth and metastasis of solid and hematologic malignancies. Our program members are working to apply their knowledge to advance new and more effective preventative interventions and cancer therapies.
– Linda Bradley, Ph.D., Program Director
A one-two punch to knockdown AML
Adams’ lab is developing novel combination therapies for Acute Myeloid Leukemia (AML). AML is a typically-lethal molecularly heterogeneous disease, with few broad-spectrum therapeutic targets. Unusually, most AML retain a normal TP53 gene, encoding the cell death protein p53, albeit in an inactive form. Drugs which activate this p53 and another class of drug called BET inhibitors both show encouraging pre-clinical activity, but limited clinical activity as single agents. Adams’ lab discovered enhanced toxicity of combined p53 activators and BET inhibitors towards AML in a culture dish and in mouse models. These results indicate that the combination of p53 activators and BET inhibitors is a novel candidate combination therapy justified for testing in human AML.
Resistant breast cancer - Blazing a new trail in options for early detection and treatment
Haricharan’s lab is developing novel approaches to overcome therapy resistance in breast cancer. Resistance to endocrine treatment occurs in ~30% of ER+ breast cancer patients resulting in ~40,000 deaths/year in the USA. Preclinical studies strongly implicate activation of a pro-growth protein, HER2 in endocrine treatment resistance. However, clinical trials of HER2 inhibitors in ER+/HER2- patients have disappointed, likely because we do not know which patients will respond to this combination. Haricharan’s lab discovered that loss of the most fundamental DNA damage repair pathway activates HER2 after endocrine treatment in ER+/HER2- breast cancer cells. Consequently, inhibiting HER2 in breast tumors that have defects in this DNA repair pathway restores sensitivity to endocrine treatment. Both diagnostic assays to test for defects in this DNA repair pathway and HER2 inhibitors are FDA-approved in cancer patients and can be easily used in the breast cancer context. Efforts are underway to initiate a clinical trial to translate these findings to the clinic.
Exposing epigenetic vulnerabilities to enhance immunotherapy response
Bradley is collaborating with Spruck (Tumor Initiation and Maintenance Program) to harness epigenetic dysregulation for immune therapy. Repetitive elements (REs), which include ancient retroviruses and retrotransposons embedded in our genomes, compose ∼50% of human DNA and are normally transcriptionally silenced, although the mechanism had remained elusive. Spruck’s lab identified FBXO44 as an essential repressor of REs in cancer cells. FBXO44 bound H3K9me3-modified nucleosomes at the replication fork and recruited an enzymatic complex that included H3K9me3 methyltransferase SUV39H1 to transcriptionally silence REs post-DNA replication. FBXO44/SUV39H1 inhibition reactivated REs, leading to DNA replication stress and stimulation of antiviral pathways and interferon (IFN) signaling in cancer cells to promote decreased tumorigenicity, increased immunogenicity, and enhanced immunotherapy response. Together, Bradley and Spruck showed that FBXO44 expression inversely correlated with replication stress, antiviral pathways, IFN signaling, and cytotoxic T cell infiltration in human cancers, while a FBXO44-immune gene signature predicted a favorable immunotherapy response in cancer patients. FBXO44/SUV39H1 were dispensable in normal cells indicating a therapeutic window for cancer treatment. Collectively, FBXO44/SUV39H1 are crucial repressors of RE transcription and their inhibition has antitumor potential as a stand-alone therapy or enhancer of immunotherapy.
Shen JZ, Qiu Z, Wu Q, Finlay D, Garcia G, Sun D, Rantala J, Barshop W, Hope JL, Gimple RC, Sangfelt O, Bradley LM, Wohlschlegel J, Rich JN, Spruck C
Cell 2021 Jan 21 ;184(2):352-369.e23
Hurtado de Mendoza T, Mose ES, Botta GP, Braun GB, Kotamraju VR, French RP, Suzuki K, Miyamura N, Teesalu T, Ruoslahti E, Lowy AM, Sugahara KN
Nat Commun 2021 Mar 9 ;12(1):1541
Latif AL, Newcombe A, Li S, Gilroy K, Robertson NA, Lei X, Stewart HJS, Cole J, Terradas MT, Rishi L, McGarry L, McKeeve C, Reid C, Clark W, Campos J, Kirschner K, Davis A, Lopez J, Sakamaki JI, Morton JP, Ryan KM, Tait SWG, Abraham SA, Holyoake T, Higgins B, Huang X, Blyth K, Copland M, Chevassut TJT, Keeshan K, Adams PD
Nat Commun 2021 Jan 11 ;12(1):241
Folic acid-mediated fibrosis is driven by C5a receptor 1-mediated activation of kidney myeloid cells.
Sahu RK, Xavier S, Chauss D, Wang L, Chew C, Taylor R, Stallcup WB, Ma JZ, Kazemian M, Afzali B, Köhl J, Portilla D
Am J Physiol Renal Physiol 2022 Jun 1 ;322(6):F597-F610
Btla signaling in conventional and regulatory lymphocytes coordinately tempers humoral immunity in the intestinal mucosa.
Stienne C, Virgen-Slane R, Elmén L, Veny M, Huang S, Nguyen J, Chappell E, Balmert MO, Shui JW, Hurchla MA, Kronenberg M, Peterson SN, Murphy KM, Ware CF, Šedý JR
Cell Rep 2022 Mar 22 ;38(12):110553
Peterson CT, Perez Santiago J, Iablokov SN, Chopra D, Rodionov DA, Peterson SN
Curr Microbiol 2022 Mar 14 ;79(5):128
Developmentally distinct CD4(+) T(reg) lineages shape the CD8(+) T cell response to acute Listeria infection.
Dolina JS, Lee J, Moore EL, Hope JL, Gracias DT, Matsutani T, Chawla A, Greenbaum JA, Linden J, Schoenberger SP
Proc Natl Acad Sci U S A 2022 Mar 8 ;119(10):e2113329119
Garancher A, Suzuki H, Haricharan S, Chau LQ, Masihi MB, Rusert JM, Norris PS, Carrette F, Romero MM, Morrissy SA, Skowron P, Cavalli FMG, Farooq H, Ramaswamy V, Jones SJM, Moore RA, Mungall AJ, Ma Y, Thiessen N, Li Y, Morcavallo A, Qi L, Kogiso M, Du Y, Baxter P, Henderson JJ, Crawford JR, Levy ML, Olson JM, Cho YJ, Deshpande AJ, Li XN, Chesler L, Marra MA, Wajant H, Becher OJ, Bradley LM, Ware CF, Taylor MD, Wechsler-Reya RJ
Nat Neurosci 2022 Jan ;25(1):127
Bhat N, Virgen-Slane R, Ramezani-Rad P, Leung CR, Chen C, Balsells D, Shukla A, Kao E, Apgar JR, Fu M, Ware CF, Rickert RC
J Exp Med 2021 May 3 ;218(5)