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Sandra McAllister, Ph.D.
Assistant Professor of Medicine, Harvard Medical School

Brigham and Women's Hospital
Department of Medicine
Hematology
75 Francis Street
Boston, MA 02115

Research Location: Harvard Institute of Medicine

Research Email: smcallister1@bwh.harvard.edu

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Research Narrative:

Recurrence of cancer in the form of metastatic disease accounts for more than 90% of cancer
deaths; however, tumor metastasis is considered an inefficient process whereby disseminated
tumor cells remain undetected for protracted periods of time. Remarkably little is known about
processes that serve to convert indolent tumors – such as the metastases that disseminate from a
primary tumor – into overt, life-threatening tumors. Our research is focused on identifying systemic
factors that contribute to tumor progression and finding ways to interdict their function. It is our
hope that such information will ultimately lead to new therapies to treat cancer patients.

Discovery of Systemic Instigation
Our prior work lead to the discovery that certain indolent tumor cells can respond to systemic cues
to become overt, detectable tumors. These systemic cues were actually generated by aggressively
growing tumors located at distant anatomical sites. Thus, we found that human breast carcinomas
(termed “Instigators”) facilitate growth of otherwise-indolent tumor cells and micrometastases
(termed “Responders”) located in different anatomical sites. We termed this action-at-a-distance
“Systemic Instigation”. Therefore, we think of cancer as a disease that is capable of actively
perturbing as well as responding to the systemic environment. The view that tumor cells escape
detection and remain indolent for protracted periods is not limited to disseminated tumor cells, but
can also apply to primary tumors.

Understanding the role of circulating cytokines in cancer progression
We identified a molecular mediator that is necessary but not sufficient for systemic instigation –
tumor-derived osteopontin (OPN). The relevance of OPN expression to human cancer
pathogenesis has been revealed by studies showing that OPN expression levels are elevated in
aggressive tumors types when compared with normal tissue or low-grade tumors and is included
among lists of genes that predict poor prognosis in patients with various types of cancer. Other
studies have shown that elevated levels of soluble OPN in the blood of many cancer patients are
correlated with reduced survival. We identified a novel role for OPN in supporting distant tumor
outgrowth: soluble OPN secreted from instigating tumors acts in an endocrine fashion to perturb
cells in the bone marrow that are subsequently mobilized into the circulation and recruited into the
stroma of tumors at secondary sites, ultimately resulting in the outgrowth of these distant,
otherwise-indolent tumors (see model). Our observations that tumor-derived OPN is not sufficient
on its own to facilitate outgrowth of distant indolent tumors suggest that other, still-unidentified
factors cooperate with OPN to mediate systemic instigation. It is likely that a variety of endocrine
and paracrine factors, working in concert, are necessary for various aspects of the systemic
instigation cascade. We plan to take various experimental approaches to identify such factors.
Thus, we hope to build a molecular framework for understanding the systemic instigation process.

Understanding the role of bone marrow derived cells in cacer progression
Systemic instigation is accompanied by the incorporation of bone marrow derived cells into the
microenvironment of the distant, once-indolent tumors. We found that bone marrow cells are rendered pro-tumorigenic even prior to their mobilization and that these activated bone marrow cells mimic the
systemic effects imparted by instigating tumors. Together with our colleagues in the Hematology
Division of Brigham and Women’s Hospital, we are focusing our research efforts on these bone
marrow cell type(s) and how they are affected by endocrine factors released into the circulation by
instigating tumors.


Education:
Whitehead Institute for Biomedical research, 2002-2009, Postdoctoral Fellow
Washington University, 2002, Ph.D.

Honors/Awards:
Presidential Early Career Award for Scientists and Engineers
Gertrude B. Elion Cancer Research Award
American Cancer Society Scholar

Publications (Pulled from Harvard Catalyst Profiles):

1. Castaño Z, San Juan BP, Spiegel A, Pant A, DeCristo MJ, Laszewski T, Ubellacker JM, Janssen SR, Dongre A, Reinhardt F, Henderson A, Del Rio AG, Gifford AM, Herbert ZT, Hutchinson JN, Weinberg RA, Chaffer CL, McAllister SS. IL-1ß inflammatory response driven by primary breast cancer prevents metastasis-initiating cell colonization. Nat Cell Biol. 2018 Sep; 20(9):1084-1097.

2. Ubellacker JM, Baryawno N, Severe N, DeCristo MJ, Sceneay J, Hutchinson JN, Haider MT, Rhee CS, Qin Y, Gregory WM, Garrido-Castro AC, Holen I, Brown JE, Coleman RE, Scadden DT, McAllister SS. Modulating Bone Marrow Hematopoietic Lineage Potential to Prevent Bone Metastasis in Breast Cancer. Cancer Res. 2018 Sep 15; 78(18):5300-5314.

3. Goel S, DeCristo MJ, McAllister SS, Zhao JJ. CDK4/6 Inhibition in Cancer: Beyond Cell Cycle Arrest. Trends Cell Biol. 2018 Nov; 28(11):911-925.

4. Lee JJ, van de Ven RAH, Zaganjor E, Ng MR, Barakat A, Demmers JJPG, Finley LWS, Gonzalez Herrera KN, Hung YP, Harris IS, Jeong SM, Danuser G, McAllister SS, Haigis MC. Inhibition of epithelial cell migration and Src/FAK signaling by SIRT3. Proc Natl Acad Sci U S A. 2018 07 03; 115(27):7057-7062.

5. Olive JF, Qin Y, DeCristo MJ, Laszewski T, Greathouse F, McAllister SS. Accounting for tumor heterogeneity when using CRISPR-Cas9 for cancer progression and drug sensitivity studies. PLoS One. 2018; 13(6):e0198790.

6. Goel S, DeCristo MJ, Watt AC, BrinJones H, Sceneay J, Li BB, Khan N, Ubellacker JM, Xie S, Metzger-Filho O, Hoog J, Ellis MJ, Ma CX, Ramm S, Krop IE, Winer EP, Roberts TM, Kim HJ, McAllister SS, Zhao JJ. CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017 08 24; 548(7668):471-475.

7. Sceneay J, McAllister SS. The skinny on obesity and cancer. Nat Cell Biol. 2017 Jul 28; 19(8):887-888.

8. Ubellacker JM, Haider MT, DeCristo MJ, Allocca G, Brown NJ, Silver DP, Holen I, McAllister SS. Zoledronic acid alters hematopoiesis and generates breast tumor-suppressive bone marrow cells. Breast Cancer Res. 2017 03 06; 19(1):23.

9. Olsen SN, Wronski A, Castaño Z, Dake B, Malone C, De Raedt T, Enos M, DeRose YS, Zhou W, Guerra S, Loda M, Welm A, Partridge AH, McAllister SS, Kuperwasser C, Cichowski K. Loss of RasGAP Tumor Suppressors Underlies the Aggressive Nature of Luminal B Breast Cancers. Cancer Discov. 2017 02; 7(2):202-217.

10. Henry WS, Laszewski T, Tsang T, Beca F, Beck AH, McAllister SS, Toker A. Aspirin Suppresses Growth in PI3K-Mutant Breast Cancer by Activating AMPK and Inhibiting mTORC1 Signaling. Cancer Res. 2017 02 01; 77(3):790-801.