Abstract 364: The molecular profiles of disseminated tumor cells in a Patient Derived Xenograft model recapitulate those found in patient bone marrow
Authors: Pillai Sreeraj G. , Li Shunqiang , Siddappa Chidananda M. , Watson Mark A. , Fleming Timothy P. , Ellis Matthew J. , Aft Rebecca L. 
Published: August 2015

Objective

Disseminated tumor cells (DTCs) found in the bone marrow (BM) of breast cancer patients portends a poor prognosis. BM DTCs are thought to be intermediaries in the metastatic process and may exhibit molecular features different from the primary tumor. Using Patient Derived Xenograft system, we report the presence of transcript associated with DTCs and their correlation to distant disease development.

Experimental procedures

After informed consent, human breast adenocarcinomas were prospectively collected from 5 patients with estrogen receptor negative/Her2 negative tumors and implanted into NOD/SCID mouse mammary fat pad as previous described. BM was collected from the femur and tibia from mice at varying passages of the tumors and analyzed for human-specific transcripts by qRT-PCR. Human gene expression array analysis (Affymetrix Human gene 1.0ST) was performed on the BMs from all WHIM17 mice, control non-tumor bearing mice, breast cancer patients and that of healthy volunteers.

Results

BM was screened from 18 tumor bearing mice for the presence of DTCs of which 10 mice developed metastatic tumors. All mice developed from one patient line (WHIM17) developed metastatic tumors. Further microanalysis of WHIM 17 BM showed 300 genes upregulated over 10 fold in their BM compared to non-tumor bearing mice. 7 of these genes were detected in the BM of breast cancer patients but completely absent in BM of healthy volunteers. They are TNFRSF17, CD226, HIST1H4E, MDM2, TFAM, DDT, and RPS20. The presence of these transcripts was confirmed by qRT-PCR and was detected in the BM of mice which developed metastatic tumors. Of the 32 genes which we found significantly upregulated in the BM of stage II/III breast cancer patients prior to treatment who subsequently developed metastatic tumors compared to similar patients who did not develop metastatic disease, DCSR3 and STAM2 were upregulated in all WHIM17 mice.

Conclusion

The presence of DTCs in the BM and its association with metastatic outcome was observed in the PDX model system. Our results provide an experimental support for the clinical association of DTCs in the BM of early stage breast cancer patients with recurrent disease development. We believe the PDX mice recreate a more clinically relevant model compared to other xenograft models. Moreover, using this system, we have identified new targetable genes associated with DTCS.

Citation Format: Sreeraj G. Pillai, Shunqiang Li, Chidananda M. Siddappa, Mark A. Watson, Timothy P. Fleming, Matthew J. Ellis, Rebecca L. Aft. The molecular profiles of disseminated tumor cells in a Patient Derived Xenograft model recapitulate those found in patient bone marrow. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 364. doi:10.1158/1538-7445.AM2015-364