Un­rav­el­ing the Com­plex­i­ties of Can­cer through More Hu­man-rel­e­vant Mod­els

The cur­rent par­a­digm in pre­clin­i­cal test­ing for de­vel­op­ing can­cer ther­a­peu­tics is fail­ing. On­col­o­gy drug can­di­dates are cur­rent­ly the least like­ly type of ther­a­peu­tic to suc­ceed in clin­i­cal tri­als, with on­ly 5.1% of Phase I can­di­dates go­ing on to re­ceive FDA ap­proval. A ma­jor rea­son for this high at­tri­tion rate is the pre­clin­i­cal in vit­ro and in vi­vo mod­els that can­cer re­searchers re­ly on. While con­ven­tion­al in vit­ro can­cer mod­els can mim­ic some parts of hu­man phys­i­ol­o­gy, they of­ten lack crit­i­cal fac­tors such as cel­lu­lar het­ero­gene­ity and a dy­nam­ic, na­tive mi­croen­vi­ron­ment. As such, sci­en­tists con­tin­ue to re­ly on an­i­mal mod­els; how­ev­er, an­i­mals of­ten lack hu­man rel­e­vance, al­low­ing in­ef­fec­tive and tox­ic drugs to en­ter clin­i­cal tri­als. To cre­ate more suc­cess­ful drug de­vel­op­ment pro­grams, sci­en­tists need mod­els that pro­vide a more com­pre­hen­sive and hu­man-rel­e­vant view of can­cer pro­gres­sion.

The Im­por­tance of Un­der­stand­ing the Tu­mor Mi­croen­vi­ron­ment

There is grow­ing ev­i­dence that the tu­mor mi­croen­vi­ron­ment (TME) is a cru­cial mod­u­la­tor of can­cer growth, mi­gra­tion, an­gio­gen­e­sis, im­muno­sur­veil­lance eva­sion, and ther­a­py re­sis­tance. The TME is com­posed of ex­tra­cel­lu­lar ma­trix (ECM) and var­i­ous non-ma­lig­nant cell types, in­clud­ing en­dothe­lial, mes­enchy­mal (e.g., fi­brob­lasts and adipocytes) and im­mune cells (e.g., lym­pho­cytes, mono­cytes, and neu­trophils), all of which in­ter­act with tu­mor cells via se­cre­tion of mol­e­cules such as growth fac­tors, cy­tokines, ex­tra­cel­lu­lar vesi­cles, and miR­NAs (Fig­ure 1). The ECM in par­tic­u­lar has a sig­nif­i­cant ef­fect on the be­hav­ior of cells, as it pro­vides struc­tur­al and bio­chem­i­cal sup­port. Dur­ing can­cer pro­gres­sion, the stiff­ness of the ECM in­flu­ences cells’ pro­lif­er­a­tion, sur­vival, mi­gra­tion, and dif­fer­en­ti­a­tion. Thus, un­der­stand­ing the TME is key to un­der­stand­ing over­all can­cer pro­gres­sion and de­vel­op­ing ef­fec­tive ther­a­pies.

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Fig­ure 1. The tu­mor mi­croen­vi­ron­ment.

The Need for Bet­ter Mod­els

An­i­mal mod­els have tra­di­tion­al­ly been con­sid­ered the gold stan­dard in dis­ease re­search and drug de­vel­op­ment, de­spite the high fail­ure rate of drugs tran­si­tion­ing to the clin­ic. To im­prove the trans­lata­bil­i­ty of an­i­mal mod­els for can­cer re­search, hu­man tu­mors are of­ten graft­ed in­to an­i­mals. The xenograft mouse mod­el, for ex­am­ple, is cre­at­ed when the tis­sue of in­ter­est is im­plant­ed in­to an im­muno­com­pro­mised mouse. The or­tho­topic mouse mod­el dif­fers in that the hu­man tu­mor is graft­ed on­to the cor­re­spond­ing or­gan of in­ter­est in the mouse. While these mod­els are more dif­fi­cult to cre­ate, they are more phys­i­o­log­i­cal­ly rel­e­vant be­cause the tu­mors are grow­ing in an or­gan-spe­cif­ic TME. De­spite us­ing hu­man tu­mors, how­ev­er, xenograft and or­tho­topic mouse mod­els still have lim­it­ed hu­man rel­e­vance, as the im­mune com­po­nents and TME are an­i­mal-based and do not re­ca­pit­u­late how a tu­mor pro­gress­es in the hu­man body.

While re­searchers can cre­ate can­cer mod­els en­tire­ly from hu­man cell sources, they con­tin­ue to face chal­lenges in ful­ly re­ca­pit­u­lat­ing hu­man bi­o­log­i­cal func­tion in a dish. 2D in vit­ro mod­els are sim­ple and cost-ef­fec­tive mod­els to in­cor­po­rate in­to drug screen­ing as­says, but their sim­plic­i­ty re­sults in low phys­i­o­log­i­cal rel­e­vance. Spher­oids of­fer im­proved 3D cy­toar­chi­tec­ture, but of­ten have is­sues in uni­for­mi­ty and re­pro­ducibil­i­ty, lack stan­dard­ized as­sess­ments of growth and drug ef­fi­ca­cy, and are not high through­put for drug screen­ing.

Organoids are a pow­er­ful al­ter­na­tive to 2D cul­ture that pre­serves many of the struc­tur­al and func­tion­al traits of their in vi­vo coun­ter­parts, such as a hy­pox­ic mi­croen­vi­ron­ment, cell het­ero­gene­ity, ECM in­ter­ac­tions, and more in vi­vo-rel­e­vant gene ex­pres­sion pat­terns. Tu­mor organoids can ei­ther be de­rived from pa­tient tis­sue or en­gi­neered us­ing in­duced pluripo­tent stem cells (iP­SCs) and spe­cial cul­ture con­di­tions. Those gen­er­at­ed from iP­SCs and adult stem cells en­com­pass im­por­tant tis­sue fea­tures such as ar­chi­tec­ture, dif­fer­en­ti­at­ed cell types, and tis­sue func­tion. Tak­en to­geth­er, organoids are com­pa­ra­ble to cer­tain in vi­vo mod­els such as tra­di­tion­al ge­net­i­cal­ly en­gi­neered mouse mod­els, cell lines, and pa­tient-de­rived xenografts (PDX). How­ev­er, organoids lack an or­gan-spe­cif­ic en­vi­ron­ment that in­cludes im­mune com­po­nents, blood ves­sels, and dif­fer­ent stro­mal cells. Fi­nal­ly, growth stim­u­la­tors and in­hibitors used in the growth of organoids can af­fect drug sen­si­tiv­i­ty, gene ex­pres­sion, and cell sig­nal­ing path­ways.

A New Way For­ward: Im­prov­ing 3D Can­cer Mod­el­ing with Or­gan-Chips

Or­gan-on-a-Chip tech­nol­o­gy has been de­vel­oped to ad­dress many of the chal­lenges dis­cussed above. These mi­croflu­idic de­vices em­u­late in vi­vo phys­i­ol­o­gy and tis­sue mi­croen­vi­ron­ments in an or­gan-spe­cif­ic con­text by en­abling key cel­lu­lar pop­u­la­tions to be added to par­al­lel mi­croflu­idic chan­nels that are sep­a­rat­ed by a porous mem­brane (Fig­ure 2). Ad­di­tion­al fea­tures such as bio­me­chan­i­cal forces, ECM, and im­mune cells pro­vide a more hu­man-rel­e­vant en­vi­ron­ment for cells to be­have as they would in vi­vo.

Fig­ure 2. Schemat­ic of an Or­gan-Chip.

Re­cent ad­vances in the de­sign of Or­gan-Chip con­sum­ables have im­proved the abil­i­ty of Or­gan-Chips to ad­dress the needs of mod­el­ing the tu­mor mi­croen­vi­ron­ment. The Em­u­late Chip-A1 Ac­ces­si­ble Chip al­lows re­searchers to mod­el com­plex 3D tis­sues by in­cor­po­rat­ing gels up to 3 mm thick with­in the chip’s ac­ces­si­ble cul­ture cham­ber, in­te­grat­ing stro­ma in­to the ep­ithe­lial lay­er, cre­at­ing strat­i­fied ep­ithe­lia, and ap­ply­ing or­gan-spe­cif­ic bio­me­chan­i­cal forces (Fig­ure 3). Fur­ther com­plex­i­ty and hu­man rel­e­vance can be achieved with Chip-A1 by in­cor­po­rat­ing cir­cu­lat­ing im­mune cells such as PBM­Cs or CAR T cells.

Fig­ure 3: Ex­plod­ed view of Chip-A1 Ac­ces­si­ble Chip demon­strat­ing how it has been used to mod­el ep­ithe­lial-stro­mal in­ter­ac­tions in Bar­rett’s Esoph­a­gus.

Chip-A1 has al­ready en­abled re­searchers to bet­ter un­der­stand how the sur­round­ing mi­croen­vi­ron­ment in­flu­ences can­cer pro­gres­sion. In their on­line ar­ti­cle ti­tled ‘Ep­ithe­lial-Stro­mal In­ter­ac­tions in Bar­rett’s Esoph­a­gus Mod­eled in Hu­man Or­gan Chips,” re­searchers from the Wyss In­sti­tute for Bi­o­log­i­cal­ly In­spired En­gi­neer­ing at Har­vard Uni­ver­si­ty used a pro­to­type of Chip-A1 and found that it of­fered a new ap­proach for study­ing ep­ithe­lial-stro­mal in­ter­ac­tions and the broad­er un­der­ly­ing mech­a­nisms as­so­ci­at­ed with esophageal can­cer pro­gres­sion. The team al­so re­port­ed that this mod­el could po­ten­tial­ly serve as a tool for per­son­al­ized drug-re­sponse as­sess­ments be­tween dif­fer­ent pa­tients or ge­net­ic sub­pop­u­la­tions.


Un­der­stand­ing how the tu­mor mi­croen­vi­ron­ment con­tributes to can­cer pro­gres­sion re­mains crit­i­cal for de­vel­op­ing more ef­fec­tive ther­a­peu­tics. Or­gan-on-a-Chip tech­nol­o­gy is evolv­ing to meet the in vit­ro mod­el­ing needs for re­search ar­eas such as can­cer, which re­quire en­hanced 3D mod­els and more phys­i­o­log­i­cal­ly rel­e­vant com­pound dos­ing op­tions. Pre­clin­i­cal mod­els that en­able re­searchers to mod­el bi­ol­o­gy that is more com­plex, like the TME, will im­prove clin­i­cal trans­la­tion, and Chip-A1 will give re­searchers this ca­pa­bil­i­ty.