Aditi Khatpe

All Publications

• Role of matrix viscoelasticity in basement membrane invasion in breast cancer Alyafei, N. K., Khatpe, A. S., West, R., Chaudhuri, O. CELL PRESS. 2026

  View details for Web of Science ID 001717073500023

• Author Correction: Single-nucleus chromatin accessibility and transcriptomic map of breast tissues of women of diverse genetic ancestry. Nature medicine Bhat-Nakshatri, P., Gao, H., Khatpe, A. S., Adebayo, A. K., McGuire, P. C., Erdogan, C., Chen, D., Jiang, G., New, F., German, R., Emmert, L., Sandusky, G., Storniolo, A. M., Liu, Y., Nakshatri, H. 2025; 31 (5): 1714

  View details for DOI 10.1038/s41591-025-03681-z

  View details for PubMedID 40195453

  View details for PubMedCentralID PMC12092289

• Single-nucleus chromatin accessibility and transcriptomic map of breast tissues of women of diverse genetic ancestry. Nature medicine Bhat-Nakshatri, P., Gao, H., Khatpe, A. S., Adebayo, A. K., McGuire, P. C., Erdogan, C., Chen, D., Jiang, G., New, F., German, R., Emmert, L., Sandusky, G., Storniolo, A. M., Liu, Y., Nakshatri, H. 2024; 30 (12): 3482-3494

  Abstract

  Single-nucleus analysis allows robust cell-type classification and helps to establish relationships between chromatin accessibility and cell-type-specific gene expression. Here, using samples from 92 women of several genetic ancestries, we developed a comprehensive chromatin accessibility and gene expression atlas of the breast tissue. Integrated analysis revealed ten distinct cell types, including three major epithelial subtypes (luminal hormone sensing, luminal adaptive secretory precursor (LASP) and basal-myoepithelial), two endothelial and adipocyte subtypes, fibroblasts, T cells, and macrophages. In addition to the known cell identity genes FOXA1 (luminal hormone sensing), EHF and ELF5 (LASP), TP63 and KRT14 (basal-myoepithelial), epithelial subtypes displayed several uncharacterized markers and inferred gene regulatory networks. By integrating breast epithelial cell gene expression signatures with spatial transcriptomics, we identified gene expression and signaling differences between lobular and ductal epithelial cells and age-associated changes in signaling networks. LASP cells and fibroblasts showed genetic ancestry-dependent variability. An estrogen receptor-positive subpopulation of LASP cells with alveolar progenitor cell state was enriched in women of Indigenous American ancestry. Fibroblasts from breast tissues of women of African and European ancestry clustered differently, with accompanying gene expression differences. Collectively, these data provide a vital resource for further exploring genetic ancestry-dependent variability in healthy breast biology.

  View details for DOI 10.1038/s41591-024-03011-9

  View details for PubMedID 39122969

  View details for PubMedCentralID PMC11976273

• ETV6 is an unexplored partner of the Chr.8 q24.3 amplicon- embedded immortalizing oncogene TONSL in tumorigenesis Khatpe, A. S., Doud, E., Mosely, A., Miller, K. D., Nakshatri, H. AMER ASSOC CANCER RESEARCH. 2024

  View details for DOI 10.1158/1538-7445.AM2024-6977

  View details for Web of Science ID 001253000905344

• Signaling Pathway Alterations Driven by BRCA1 and BRCA2 Germline Mutations are Sufficient to Initiate Breast Tumorigenesis by the PIK3CAH1047R Oncogene. Cancer research communications Bhat-Nakshatri, P., Khatpe, A. S., Chen, D., Batic, K., Mang, H., Herodotou, C., McGuire, P. C., Xuei, X., Erdogan, C., Gao, H., Liu, Y., Sandusky, G., Storniolo, A. M., Nakshatri, H. 2024; 4 (1): 38-54

  Abstract

  Single-cell transcriptomics studies have begun to identify breast epithelial cell and stromal cell specific transcriptome differences between BRCA1/2 mutation carriers and non-carriers. We generated a single-cell transcriptome atlas of breast tissues from BRCA1, BRCA2 mutation carriers and compared this single-cell atlas of mutation carriers with our previously described single-cell breast atlas of healthy non-carriers. We observed that BRCA1 but not BRCA2 mutations altered the ratio between basal (basal-myoepithelial), luminal progenitor (luminal adaptive secretory precursor, LASP), and mature luminal (luminal hormone sensing) cells in breast tissues. A unique subcluster of cells within LASP cells is underrepresented in case of BRCA1 and BRCA2 mutation carriers compared with non-carriers. Both BRCA1 and BRCA2 mutations specifically altered transcriptomes in epithelial cells which are an integral part of NFκB, LARP1, and MYC signaling. Signaling pathway alterations in epithelial cells unique to BRCA1 mutations included STAT3, BRD4, SMARCA4, HIF2A/EPAS1, and Inhibin A signaling. BRCA2 mutations were associated with upregulation of IL6, PDK1, FOXO3, and TNFSF11 signaling. These signaling pathway alterations are sufficient to alter sensitivity of BRCA1/BRCA2-mutant breast epithelial cells to transformation as epithelial cells from BRCA1 mutation carriers overexpressing hTERT + PIK3CAH1047R generated adenocarcinomas, whereas similarly modified mutant BRCA2 cells generated basal carcinomas in NSG mice. Thus, our studies provide a high-resolution transcriptome atlas of breast epithelial cells of BRCA1 and BRCA2 mutation carriers and reveal their susceptibility to PIK3CA mutation-driven transformation.This study provides a single-cell atlas of breast tissues of BRCA1/2 mutation carriers and demonstrates that aberrant signaling due to BRCA1/2 mutations is sufficient to initiate breast cancer by mutant PIK3CA.

  View details for DOI 10.1158/2767-9764.CRC-23-0330

  View details for PubMedID 38059556

  View details for PubMedCentralID PMC10774565

• Stromal heterogeneity may explain increased incidence of metaplastic breast cancer in women of African descent. Nature communications Kumar, B., Khatpe, A. S., Guanglong, J., Batic, K., Bhat-Nakshatri, P., Granatir, M. M., Addison, R. J., Szymanski, M., Baldridge, L. A., Temm, C. J., Sandusky, G., Althouse, S. K., Cote, M. L., Miller, K. D., Storniolo, A. M., Nakshatri, H. 2023; 14 (1): 5683

  Abstract

  The biologic basis of genetic ancestry-dependent variability in disease incidence and outcome is just beginning to be explored. We recently reported enrichment of a population of ZEB1-expressing cells located adjacent to ductal epithelial cells in normal breasts of women of African ancestry compared to those of European ancestry. In this study, we demonstrate that these cells have properties of fibroadipogenic/mesenchymal stromal cells that express PROCR and PDGFRα and transdifferentiate into adipogenic and osteogenic lineages. PROCR + /ZEB1 + /PDGFRα+ (PZP) cells are enriched in normal breast tissues of women of African compared to European ancestry. PZP: epithelial cell communication results in luminal epithelial cells acquiring basal cell characteristics and IL-6-dependent increase in STAT3 phosphorylation. Furthermore, level of phospho-STAT3 is higher in normal and cancerous breast tissues of women of African ancestry. PZP cells transformed with HRasG12V ± SV40-T/t antigens generate metaplastic carcinoma suggesting that these cells are one of the cells-of-origin of metaplastic breast cancers.

  View details for DOI 10.1038/s41467-023-41473-6

  View details for PubMedID 37709737

  View details for PubMedCentralID PMC10502140

• TONSL Is an Immortalizing Oncogene and a Therapeutic Target in Breast Cancer. Cancer research Khatpe, A. S., Dirks, R., Bhat-Nakshatri, P., Mang, H., Batic, K., Swiezy, S., Olson, J., Rao, X., Wang, Y., Tanaka, H., Liu, S., Wan, J., Chen, D., Liu, Y., Fang, F., Althouse, S., Hulsey, E., Granatir, M. M., Addison, R., Temm, C. J., Sandusky, G., Lee-Gosselin, A., Nephew, K., Miller, K. D., Nakshatri, H. 2023; 83 (8): 1345-1360

  Abstract

  Study of genomic aberrations leading to immortalization of epithelial cells has been technically challenging due to the lack of isogenic models. To address this, we used healthy primary breast luminal epithelial cells of different genetic ancestry and their hTERT-immortalized counterparts to identify transcriptomic changes associated with immortalization. Elevated expression of TONSL (Tonsoku-like, DNA repair protein) was identified as one of the earliest events during immortalization. TONSL, which is located on chromosome 8q24.3, was found to be amplified in approximately 20% of breast cancers. TONSL alone immortalized primary breast epithelial cells and increased telomerase activity, but overexpression was insufficient for neoplastic transformation. However, TONSL-immortalized primary cells overexpressing defined oncogenes generated estrogen receptor-positive adenocarcinomas in mice. Analysis of a breast tumor microarray with approximately 600 tumors revealed poor overall and progression-free survival of patients with TONSL-overexpressing tumors. TONSL increased chromatin accessibility to pro-oncogenic transcription factors, including NF-κB and limited access to the tumor-suppressor p53. TONSL overexpression resulted in significant changes in the expression of genes associated with DNA repair hubs, including upregulation of several genes in the homologous recombination (HR) and Fanconi anemia pathways. Consistent with these results, TONSL-overexpressing primary cells exhibited upregulated DNA repair via HR. Moreover, TONSL was essential for growth of TONSL-amplified breast cancer cell lines in vivo, and these cells were sensitive to TONSL-FACT complex inhibitor CBL0137. Together, these findings identify TONSL as a regulator of epithelial cell immortalization to facilitate cancer initiation and as a target for breast cancer therapy.The chr.8q24.3 amplicon-resident gene TONSL is upregulated during the initial steps of tumorigenesis to support neoplastic transformation by increasing DNA repair and represents a potential therapeutic target for treating breast cancer.

  View details for DOI 10.1158/0008-5472.CAN-22-3667

  View details for PubMedID 37057595

  View details for PubMedCentralID PMC10107402

• TONSL is an immortalizing oncogene of the chromosome 8q24.3 amplicon and new therapeutic target in breast cancer Khatpe, A. S., Dirks, R., Bhat-Nakshatri, P., Mang, H., Batic, K., Swiezy, S., Olson, J., Rao, X., Wang, Y., Tanaka, H., Liu, S., Wan, J., Chen, D., Liu, Y., Fang, F., Althouse, S., Hilsey, E., Granatir, M. M., Addison, R., Temm, C. J., Sandusky, G., Lee-Gosselin, A., Nephew, K., Miller, K. D., Nakshatri, H. AMER ASSOC CANCER RESEARCH. 2023

  View details for DOI 10.1158/1538-7445.AM2023-5458

  View details for Web of Science ID 001008499104291

• Nexus between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer. Cancers Khatpe, A. S., Adebayo, A. K., Herodotou, C. A., Kumar, B., Nakshatri, H. 2021; 13 (3)

  Abstract

  Signaling from estrogen receptor alpha (ERα) and its ligand estradiol (E2) is critical for growth of ≈70% of breast cancers. Therefore, several drugs that inhibit ERα functions have been in clinical use for decades and new classes of anti-estrogens are continuously being developed. Although a significant number of ERα+ breast cancers respond to anti-estrogen therapy, ≈30% of these breast cancers recur, sometimes even after 20 years of initial diagnosis. Mechanism of resistance to anti-estrogens is one of the intensely studied disciplines in breast cancer. Several mechanisms have been proposed including mutations in ESR1, crosstalk between growth factor and ERα signaling, and interplay between cell cycle machinery and ERα signaling. ESR1 mutations as well as crosstalk with other signaling networks lead to ligand independent activation of ERα thus rendering anti-estrogens ineffective, particularly when treatment involved anti-estrogens that do not degrade ERα. As a result of these studies, several therapies that combine anti-estrogens that degrade ERα with PI3K/AKT/mTOR inhibitors targeting growth factor signaling or CDK4/6 inhibitors targeting cell cycle machinery are used clinically to treat recurrent ERα+ breast cancers. In this review, we discuss the nexus between ERα-PI3K/AKT/mTOR pathways and how understanding of this nexus has helped to develop combination therapies.

  View details for DOI 10.3390/cancers13030369

  View details for PubMedID 33498407

  View details for PubMedCentralID PMC7864210