Cancer evolves to due to injury to the functional parenchyma in our body. While genetic injury, in the form of chromosomal rearrangements and gene alterations, are associated with cancer initiation and progression, the host response associated with genetic injury plays a critical role in the pathogenesis of cancer. Our laboratory is dedicated to unraveling the fundamental principles governing cancer initiation, progression and metastasis, with specific emphasis on tumor microenvironment in the context of pancreatic ductal adenocarcinoma (PDAC), triple negative breast cancer (TNBC) and glioblastoma multiforme (GBM).
The efforts of the Kalluri laboratory since 1997 led to many discoveries related to mechanism of tissue injury and regeneration, vascular biology and tumor angiogenesis, and tumor microenvironment and exosomes biology (https://www.ncbi.nlm.nih.gov/pubmed/?term=kalluri+r), and some of these findings were translated into the clinic to benefit our patients. The laboratory discoveries unraveled new understanding of the biology of cancer, offered opportunities to work with pharmaceutical industry to develop new drugs, and contributed to the formation of new biotechnology companies in partnership with the institution in an effort to fight cancer. Since moving to MD Anderson Cancer Center in 2012, the research from the Kalluri laboratory has been cited 31,876 times with an h-index of 83.
The research in our laboratory continuously evolves to reflect the knowledge gained with each study completed and the emerging new scientific information. Such plasticity allows researchers in our laboratory to ask out-of-the box questions and constantly seek novel discoveries to develop new strategies in our fight against cancer. The students and post-doctoral fellows who join our laboratory bring fresh ideas and innovative concepts to initiate projects that drive their passion for discoveries. The current research focus of the laboratory is in the following areas:
1. Tumor Microenvironment in Cancer Biology and Metastasis
The laboratory continues to generate new genetically engineered mouse models to determine the functional contribution of the tumor microenvironment in cancer progression and metastasis. Using such models, we recently identified a tumor restraining role of carcinoma associated fibroblasts, and discovered functional heterogeneity of fibroblasts in the progression of pancreatic cancer. We unraveled novel mechanisms of metastasis and identified the defining functional role of tumor microenvironment in rate of cancer progression. Current projects in the laboratory are evaluating the regulatory connection(s) between genetic drivers of cancer and the impact of host stromal and immune responses in cancer progression and metastasis. Employing genomic and epigenetic analyses, single cell RNA sequencing, mass cytometry and proteomic profiling, the laboratory is developing novel connectivity networks and unraveling nodes of regulation between genetic defects in the cancer cells, and stromal fibroblasts recruitment, tumor angiogenesis/hypoxia, and innate and adaptive immunity. Such integrated approach to cancer biology is identifying novel mechanism associated with tumor progression and metastasis, leading to the identification of new vulnerabilities of cancer and new avenues for drug development.
1. Folkman J, Kalluri R. Cancer without disease. Nature 2004 Feb 26;427(6977):787.
2. Maeshima Y1, Sudhakar A, Lively JC, Ueki K, Kharbanda S, Kahn CR, Sonenberg N, Hynes RO, Kalluri R. Tumstatin, an endothelial cell-specific inhibitor of protein synthesis. Science 2002 Jan 4;295(5552):140-3.
3. Cooke VG, LeBleu VS, Keskin D, Khan Z, O'Connell JT, Teng Y, Duncan MB, Xie L, Maeda G, Vong S, Sugimoto H, Rocha RM,
Damascena A, Brentani RR, Kalluri R. Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell 2012 Jan 17;21(1):66-81.
4. Özdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, Laklai H, Sugimoto H, Kahlert C, Novitskiy SV,
De Jesus-Acosta A, Sharma P, Heidari P, Mahmood U, Chin L, Moses HL, Weaver VM, Maitra A, Allison JP, LeBleu VS, Kalluri R. Depletion
of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival. Cancer Cell 2015 Dec 14;28(6):831-833.
5. Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, Wu CC, LeBleu VS, Kalluri R. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 2015 Nov 26;527(7579):525-530.
6. Chen Y, LeBleu VS, Carstens JL, Sugimoto H, Zheng X, Malasi S, Saur D, Kalluri R. Dual
reporter genetic mouse models of pancreatic cancer identify an epithelial-to-mesenchymal transition-independent metastasis program. EMBO Mol Med. 2018 Aug 17.
2. Tissue Injury, Repair, and Regeneration
Cancer is a disease with two components: the genetic injury and the host response to repair and regenerate the damage to the organ.
The dynamic balance of these two sides of ‘cancer coin’ determines the rate of cancer progression and metastasis. If the host response to genetic defects of
cancer cells involves successful immune surveillance, extracellular matrix production and recruitment of repair and regenerative mesenchymal cells such as
fibroblasts, cancer is controlled. However, cancer cells often subjugate such host responses to aid in the growth of the tumors. For the past two
decades, our laboratory invested substantial intellectual energy to discover the principles governing the tissue injury and regeneration responses
associated with autoimmune and genetic kidney diseases, organ fibrosis, embryonic development, pregnancy disorders, and wound healing. The
comprehensive knowledge gained from such studies had a direct impact on the unraveling new biology associated with host response to cancer. Keeping the ultimate translational goals in mind, the current projects are designed to discover the governing principles of immune recognition of damaged parenchymal cells in the context chronic diseases such as organ fibrosis and cancer, and to decipher the functional heterogeneity of fibrosis-associated fibroblasts when compared with carcinoma-associated fibroblasts. Identification of functional differences in the pathogenic extracellular matrix between neoplastic and non-neoplastic diseases is offering novel insights into regulation of tumor growth and dissemination, and regulation of tumor immunity. Studies related to placental hypoxia and cytotrophoblast invasion are providing new clues as to how tumor hypoxia regulates cancer invasion and metastasis.
1. Kalluri R. The biology and function of fibroblasts in cancer. Nature Rev Cancer 2016 Aug 23;16(9):582-98.
2. Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F, Kalluri R. BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nature Medicine 2003 Jul;9(7):964-8.
3. Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, Chandraker A, Yuan X, Pu WT, Roberts AB,
Neilson EG, Sayegh MH, Izumo S, Kalluri R. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nature Medicine 2007 Aug;13(8):952-61.
4. Sugimoto H, LeBleu VS, Bosukonda D, Keck P, Taduri G, Bechtel W, Okada H, Carlson W Jr, Bey P, Rusckowski M, Tampe B,
Tampe D, Kanasaki K, Zeisberg M, Kalluri R. Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis. Nature Medicine 2012 Feb
5. LeBleu VS, Taduri G, O'Connell J, Teng Y, Cooke VG, Woda C, Sugimoto H, Kalluri R. Origin and function of myofibroblasts in kidney fibrosis. Nature Medicine 2013 Aug;19(8):1047-53.
6. Lovisa S, LeBleu VS, Tampe B, Sugimoto H, Vadnagara K, Carstens JL, Wu CC, Hagos Y, Burckhardt BC, Pentcheva-Hoang T, Nischal H, Allison JP, Zeisberg M, Kalluri R. Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nature Medicine 2015 Sep;21(9):998-1009.
3. Biology and Function of Exosomes in Cancer
Exosomes are extracellular vesicles of ~40-160nm in size and released by all cells of the human body, and all cells of the animal and plant kingdom. Our laboratory is interested in identifying the physiological function of exosomes and their role in disease states such as cancer. In the last five years, we unraveled new biology associated with exosomes. We identified functional mRNA and microRNAs in exosomes and discovered that cancer exosomes can perform cell-independent microRNA biogenesis, which aid in the transformation of normal epithelial cells. We demonstrated that cancer-derived exosomes could induce
non-tumorigenic epithelial cells to form tumors, and we are currently evaluating the mechanism(s) behind such oncogenic potential of cancer exosomes.
Our laboratory identified double stranded genomic DNA in cancer exosomes and established their utility in diagnosis of cancer. We also exploited the property of exosomes to enter other cells and identified methods to deliver cancer drug to tumors. We demonstrate the capacity of engineered exosomes to target oncogenic Kras in pancreatic cancer (iExosomes). This discovery was translated into pre-clinical studies employing organoids, patient derived xenografts, and genetically engineered mouse models of pancreatic cancer. Good manufacturing practice produced iExosomes are being moved into Phase I testing at the MD Anderson Cancer Center. Current projects are employing CRISPR-Cas9 screens to identify novel pathways associated with exosomes production/release and uptake by other cells, and to identify novel biology that can be exploited for diagnosis and treatment of cancer and other diseases.
1. Melo SA, Sugimoto H, O'Connell JT, Kato N, Villanueva A, Vidal A, Qiu L, Vitkin E, Perelman LT, Melo CA, Lucci A, Ivan C, Calin GA, Kalluri R. Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 2014 Nov 10;26(5):707-21.
2. Kahlert C, Melo SA, Protopopov A, Tang J, Seth S, Koch M, Zhang J, Weitz J, Chin L, Futreal A, Kalluri R. Identification of double-stranded genomic DNA spanning all chromosomes with mutated KRAS and p53 DNA in the serum exosomes of patients with pancreatic cancer. J Biol Chem 2014 Feb 4;289(7):3869-75.
3. Melo SA, Luecke LB, Kahlert C, Fernandez AF, Gammon ST, Kaye J, LeBleu VS, Mittendorf EA, Weitz J, Rahbari N, Reissfelder C, Pilarsky C, Fraga MF,
Piwnica-Worms D, Kalluri R. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 2015 Jul 9;523(7559):177-82.
4. Kamerkar S, LeBleu VS, Sugimoto H, Yang S, Ruivo CF, Melo SA, Lee JJ, Kalluri R. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 2017 Jun 22;546(7659):498-503.
5. Mendt M, Kamerkar S, Sugimoto H, McAndrews KM, Wu CC, Gagea M, Yang S, Blanko EVR, Peng Q, Ma X, Marszalek JR, Maitra A, Yee C, Rezvani K, Shpall E, LeBleu VS, Kalluri R. Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI Insight 2018 Apr 19;3(8).
Training in the Kalluri Laboratory:
The laboratory has trained over 80 post-doctoral fellows (about 50% physician-scientists), 13 graduate students, and 33 undergraduate and high
school students. The research discoveries by our students and fellows led to clinical trials and collaborations with many academic laboratories and biopharmaceutical companies. Team work and integrity is central to our laboratory research culture. Trainees are encouraged to innovate, discover, and pursue bold and out-the-box questions. Each student and fellow is encouraged and trained to conduct paradigm-shifting research that can bring forward new basic science discoveries and help our patients. Students are provided freedom to think freely and pursue their research passion. Such research pursuit is appropriately supported and mentored by the PI, as well as hands-on training and supervision by the senior fellows, and other technology experts in the laboratory. The laboratory is an inter-dependent team that works diligently to help one another and foster laboratory collaborations.
TSA multiplex imaging analysis of human PDAC tissue to identify 8 different tumor microenvironment components in a single paraffin section. © Nature Communications
During renal fibrosis a partial epithelial-to-mesenchymal program results in loss of normal renal parenchyma function, contributing to the fibrotic process; this program can be genetically targeted to reverse established disease. The image depicts immunostaining of the organic anion transporter OAT3/SLC22A6 (pink) and nuclei (DAPI, cyan) in normal murine kidney tissue. © Nature Medicine